High concentration olopatadine ophthalmic composition

ABSTRACT

The present invention is an ophthalmic composition containing a relatively high concentration of olopatadine. The composition is typically an ophthalmic aqueous solution containing relatively high concentrations of olopatadine solubilized within the solution. The composition is preferably capable of providing enhanced relief from symptoms of ocular allergic conjunctivitis, particularly late phase symptoms of ocular allergic conjunctivitis.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation application of U.S. Utility patentapplication Ser. No. 13/475,607 filed May 18, 2012 (now allowed), whichclaims priority based on U.S. Provisional Patent Application Ser. No.61/487,789 filed May 19, 2011 and U.S. Provisional Patent ApplicationSer. No. 61/548,957 filed Oct. 19, 2011.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to an ophthalmic composition containing arelatively high concentration of olopatadine. More particularly, thepresent invention relates to an ophthalmic aqueous solution containing arelatively high concentration of solubilized olopatadine wherein thesolution is capable of providing enhanced relief from symptoms of ocularallergic disorders (e.g., conjunctivitis) in the early phase, the latephase or preferably both phases.

BACKGROUND OF THE INVENTION

Individuals suffering from allergic conjunctivitis experience symptomssuch as ocular irritation, itchiness, redness and the like. It has beenfound that these symptoms are significantly reduced using topicalophthalmic solutions containing olopatadine. Such solutions are soldunder the tradenames PATANOL® and PATADAY®, which are both commerciallyavailable from Alcon Laboratories, Inc., Fort Worth, Tex.

These marketed solutions were generally believed to be the mostefficacious products known for addressing symptoms of allergicconjunctivitis. Surprisingly, and as discussed further below, it hasbeen discovered that relatively high concentration solutions ofolopatadine provide significantly improved reduction of late phaseocular allergic conjunctivitis symptoms in addition to relief from earlyphase symptoms. Even more surprising, it has been discovered that suchhigh concentrations of olopatadine also provide significantly improvedreduction of redness in the early phase. Further, it has been discoveredthat enhanced relief from these early and late phase symptoms can beachieved through once a day dosing of relatively high concentrationolopatadine solution as opposed to greater dosing frequencies.

The discovery of improved reduction of early and late phase symptoms isquite significant and desirable for individuals suffering from allergicconjunctivitis. Generally, these discoveries can provide patientsgreater relief from itching and provide better aesthetic appearance tothe eye. Further, avoiding more frequent dosing is more convenient forpatients and helps assure better compliance. Further yet, improved earlyprevention and/or reduction of redness is particularly desirable sincepatients generally have a desire to keep as much redness out of theireyes as possible.

The discovery that relatively high concentration solutions ofolopatadine can relieve late phase ocular allergic conjunctivitissymptoms provides hope to sufferers of ocular allergic conjunctivitisthat a single dose of olopatadine per day could provide a substantialdegree of full day relief from their symptoms. However, the developmentof a multi-dose ophthalmic solution that includes high concentrations ofolopatadine necessary to achieve desired levels of efficacy is extremelydifficult and complex.

Solubilizing high concentrations of olopatadine in a stable manner hasproven difficult by itself. Olopatadine, by itself, is only soluble inwater (pH about 7.0) at room temperature up to a concentration of about0.18 w/v %. However, it is desirable to achieve solubilization of muchhigher concentrations of olopatadine in an effort to treat late phaseallergic conjunctivitis.

Solubilizing such higher concentrations of olopatadine has provendifficult. As one example, excipients such as polyethylene glycol (PEG)400 and polyvinylpyrrolidone (PVP), when used at reasonably desirableconcentrations, have proven incapable, alone or in combination, ofsolubilizing sufficient concentrations of olopatadine in compositionshaving approximately neutral pH. Thus, innovation is required tosolubilize a sufficient concentration of olopatadine.

In the process of such innovation, is has been discovered that highermolecular weight PEGs such as PEG 6000 can significantly enhancesolubility of olopatadine. However, such PEGs cause risk of discomfortwhen administered to humans. It has also been discovered thatcyclodextrins, such as hydroxypropyl-γ-cyclodextrin,hydroxypropyl-β-cyclodextrin and sulfoalkyl ether-β-cyclodextrin, havethe ability to solubilize significantly higher concentrations ofolopatadine. However, use of undesirably high concentrations ofcyclodextrins has been found to reduce olopatadine efficacy and/orpreservation efficacy of solutions. As such, still further innovationwas needed to create a desirable olopatadine formulation that not onlysolubilized sufficient amounts of olopatadine, but also allowed theformulation to achieve other desirable pharmaceutical characteristics.

Thus, the present invention is directed at an ophthalmic compositionthat can provide high concentrations of olopatadine topically to theeye. Further, the present invention is directed to such a compositionwherein the olopatadine is solubilized in solution in a stable manner,the composition exhibits consistent efficacy against late phase symptomsof allergic conjunctivitis, the composition exhibits sufficientantimicrobial activity to provide desired levels of preservationefficacy or any combination thereof

SUMMARY OF THE INVENTION

The present invention is directed to an ophthalmic composition fortreatment of allergic conjunctivitis. The composition will include arelatively high concentration of olopatadine, preferably at least 0.67w/v % olopatadine, preferably dissolved in solution. The compositionwill typically include a cyclodextrin, and more particularly, aγ-cyclodextrin derivative and/or a β-cyclodextrin derivative to aid insolubilizing the olopatadine. The cyclodextrin derivative is preferablyhydroxypropyl-γ-cyclodextrin (HP-γ-CD), hydroxypropyl-β-cyclodextrin(HP-β-CD), sulfoalkyl ether β-cyclodextrin (SAE-β-CD)(e.g., sulfobutylether β-cyclodextrin (SBE-β-CD)), or a combination thereof. Thecomposition will typically include a lactam polymer (e.g.,polyvinylpyrrolidone (PVP)) to aid in the solubilization of theolopatadine. The composition will also typically include a polyether(e.g., polyethylene glycol (PEG)) for enhancing solubility and/or aidingin achieving the desired tonicity. It is generally desirable for thecomposition to be disposed in an eyedropper, have a pH of 5.5 to 8.0, tohave an osmolality of 200 to 450, to have a viscosity of 10 to 200 cpsor any combination thereof. The composition will also typically includea preservative to allow the composition to achieve United States and/orEuropean Pharmacopeia preservation standards. Preferred preservativesinclude a polymeric quaternary ammonium compound, such aspolyquaternium-1, and benzalkonium chloride. The composition alsotypically includes borate and/or polyol to aid in achieving desiredpreservation.

The present invention also contemplates a method of treating ocularallergy symptoms. The method will include topically applying acomposition having a defined combination of the characteristicsdescribed above to an eye of a human. This step of topically applyingthe composition preferably includes dispensing an eyedrop from aneyedropper.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of mean conjunctival redness determined by aconjunctival allergen challenge (CAC) at 27 minutes.

FIG. 2 is a graph of mean conjunctival redness determined by aconjunctival allergen challenge (CAC) at 16 hours.

FIG. 3 is a graph of mean total redness determined by a conjunctivalallergen challenge (CAC) at 24 hours.

FIG. 4 is a graph of mean ocular itching determined by a conjunctivalallergen challenge (CAC) at 24 hours.

FIG. 5 is a graph of mean conjunctival redness determine by aconjunctival allergen challenge (CAC) at 24 hours.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is predicated upon the provision of an ophthalmiccomposition for treatment of allergic conjunctivitis. The ophthalmiccomposition is preferably an aqueous solution. The ophthalmiccomposition includes a relatively high concentration of olopatadinesolubilized in aqueous solution. The ophthalmic composition alsoincludes a unique set of excipients for solubilizing the olopatadinewhile maintaining comfort of the composition and/or efficacy of thecomposition in treating symptoms associate with allergic conjunctivitis,particularly symptoms associated with late phase allergicconjunctivitis. Preferably, the composition exhibits improved late phaseefficacy in reducing ocular itching, ocular redness or both. Thecomposition also preferably exhibits improved early phase efficacy inreducing ocular redness relative to vehicle and/or relative to lowerconcentrations of olopatadine. In a preferred embodiment, the ophthalmiccomposition is a multi-dose ophthalmic composition that also exhibits arequired degree of preservation efficacy.

Unless indicated otherwise, all component amounts (i.e., concentrations)are presented on a weight volume percent (w/v %) basis and allreferences to concentrations of olopatadine are to olopatadine freebase.

Olopatadine is a known compound that can be obtained by the methodsdisclosed in U.S. Pat. No. 5,116,863, the entire contents of which arehereby incorporated by reference in the present specification for allpurposes. The formulation of the present invention contains at least0.50%, more typically at least 0.55%, more typically at least 0.6% or0.65%, even more typically at least 0.67% or 0.68%, still more typicallyat least 0.7%, possibly at least 0.75% and even possibly at least 0.85%but typically no greater than 1.5% more typically no greater than 1.0%,still more typically no greater than 0.8%, possibly no greater than0.75% and even possibly no greater than 0.72% of olopatadine whereconcentrations of olopatadine typically represent concentrations ofolopatadine in free base form if the olopatadine is added to thecomposition as a salt. These lower limits of concentrations ofolopatadine are particularly important since it has been found thatefficacy of olopatadine in aqueous ophthalmic solutions in reducing latephase allergy symptoms and enhanced reduction of early phase rednessbegins to show improvement at concentrations greater than 0.5 w/v % ofolopatadine and begins to show statistically significant improvements inreducing late phase allergy symptoms at concentrations of about 0.7 w/v% olopatadine and above (e.g., at least 0.65 w/v %, at least 0.67 w/v %or at least 0.68 w/v %). Most preferably, the concentration of theolopatadine in the composition is 0.7 w/v %.

Generally, olopatadine will be added in the form of a pharmaceuticallyacceptable salt. Examples of the pharmaceutically acceptable salts ofolopatadine include inorganic acid salts such as hydrochloride,hydrobromide, sulfate and phosphate; organic acid salts such as acetate,maleate, fumarate, tartrate and citrate; alkali metal salts such assodium salt and potassium salt; alkaline earth metal salts such asmagnesium salt and calcium salt; metal salts such as aluminum salt andzinc salt; and organic amine addition salts such as triethylamineaddition salt (also known as tromethamine), morpholine addition salt andpiperidine addition salt. The most preferred form of olopatadine for usein the solution compositions of the present invention is thehydrochloride salt of(Z)-11-(3-dimethylaminopropylidene)-6,11-dihydro-dibenz-[b,e]oxepin-2-aceticacid. When olopatadine is added to the compositions of the presentinvention in this salt form, 0.77% olopatadine hydrochloride isequivalent to 0.7% olopatadine free base, 0.88% olopatadinehydrochloride is equivalent to 0.8% olopatadine free base, and 0.99%olopatadine hydrochloride is equivalent to 0.9% olopatadine free base.

Generally, it is preferred that the entire concentration of olopatadineis dissolved in the composition as a water based or aqueous solution.However, it is contemplated that olopatadine could be only partiallydissolved. For example, a portion of the olopatadine could be insolution with the remainder being in suspension.

The composition of the present invention also preferably includescyclodextrin derivative and more preferably β-cyclodextrin derivative,γ-cyclodextrin derivative or both to aid in solubilizing the olopatadine(i.e., as a solubilizer). The β-cyclodextrin derivative, γ-cyclodextrinderivative or combination thereof is typically present in thecomposition at a concentration that is at least 0.5% w/v, more typicallyat least 1.0% w/v and even possibly at least 1.3% w/v, but is typicallyno greater than 4.0% w/v, typically no greater than 3.2% w/v and evenpossibly no greater than 2.8% w/v. Preferably, the total concentrationof cyclodextrin is from 0.9 w/v % to 3.2 w/v %.

The specific amount of β-cyclodextrin derivative, γ-cyclodextrinderivative or combination thereof in a particular composition willtypically depend upon the type or combination of types of derivativesused. One particularly desirable β-cyclodextrin derivative is a hydroxyalkyl-β-cyclodextrin such as hydroxypropyl-β-cyclodextrin (HP-β-CD). Oneparticularly desirable γ-cyclodextrin derivative is a hydroxyalkyl-γ-cyclodextrin such as hydroxypropyl-γ-cyclodextrin (HP-γ-CD).Another particularly desirable β-cyclodextrin derivative is sulfoalkylether-β-cyclodextrin (SAE-β-CD), particularly sulfobutylether-β-cyclodextrin (SBE-β-CD). It is contemplated that a combinationof hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin and/orsulfoalkyl ether-β-cyclodextrin derivative may be employed in a singlecomposition, but it is typically desirable to use only one of the threeas the sole or substantially the sole (i.e., at least 90% by weight ofthe cyclodextrin component) cyclodextrin derivative.

When HP-β-CD is employed as the sole or substantially soleβ-cyclodextrin derivative, it is typically present in the composition ata concentration that is at least 0.5% w/v, more typically at least 1.0%w/v and even more typically at least 1.3% w/v, but is typically nogreater than 3.0% w/v, typically no greater than 2.2% w/v and istypically no greater than 1.7% w/v. When HP-γ-CD is employed as the soleor substantially sole γ-cyclodextrin derivative, it is typically presentin the composition at a concentration that is at least 0.5% w/v, moretypically at least 1.0% w/v and even more typically at least 1.3% w/v,but is typically no greater than 3.0% w/v, typically no greater than2.2% w/v and is typically no greater than 1.7% w/v. When SAE-β-CD isemployed as the sole or substantially sole β-cyclodextrin derivative, itis typically present in the composition at a concentration that is atleast 0.3% w/v, more typically at least 0.7% w/v and even more typicallyat least 0.9% w/v, but is typically no greater than 2.4% w/v, typicallyno greater than 1.5% w/v and is typically no greater than 1.1% w/v.

HP-β-CD is a commodity product and pharmaceutical grades of HP-β-CD canbe purchased from a variety of sources, for example, from SIGMA ALDRICH,which has its corporate headquarters in St. Louis, Mo. or ASHLANDSPECIALTY INGREDIENTS, headquartered in Wayne, N.J. HP-γ-CD is acommodity product and pharmaceutical grades of HP-γ-CD can be purchasedfrom a variety of sources, for example, from SIGMA ALDRICH, which hasits corporate headquarters in St. Louis, Mo. or ASHLAND SPECIALTYINGREDIENTS, headquartered in Wayne, N.J. SAE-β-CD can be formed basedupon the teachings of U.S. Pat. Nos. 5,134,127 and 5,376,645, which areincorporated herein by reference for all purposes. It is generallypreferred, however, to use purified SAE-β-CD. Purified SAE-β-CD ispreferably formed in accordance with the teachings of U.S. Pat. Nos.6,153,746 and 7,635,773. Purified SAE-β-CD is commercially availableunder the tradename CAPTISOL® from CyDex Pharmaceuticals, Inc., Lenexa,Kans.

With regard to γ-cyclodextrin derivative and β-cyclodextrin derivativein the composition of the present invention, it has been found thatundesirably high concentrations of γ-cyclodextrin derivative and/orβ-cyclodextrin derivative can significantly interfere with preservationefficacy of the compositions, particularly when benzalkonium chlorideand/or polymeric quaternary ammonium compound are employed aspreservation agents. Thus, lower concentrations of γ-cyclodextrinderivative and/or β-cyclodextrin derivative are typically preferred.Advantageously, it has also been found, however, that the ability of theγ-cyclodextrin derivative and β-cyclodextrin derivatives in solubilizingolopatadine is very strong and relatively low concentrations ofγ-cyclodextrin derivative and/or β-cyclodextrin derivative cansolubilize significant concentrations of olopatadine in aqueoussolution. As such, more desirable and reasonable concentrations ofadditional solubilizing agent can be used to aid in solubilizing thedesired amounts of olopatadine.

Further, it has been found that a composition formed using a combinationof solubilizing agents such as polyvinylpyrrolidone, tyloxapol,polyethylene glycol and others to solubilize relatively highconcentrations of olopatadine in the absence of γ-cyclodextrinderivative and/or β-cyclodextrin derivative will typically lack longterm stability or shelf life. It has been found that such a compositionwill typically begin to precipitate after undesirably short periods oftime. Thus, it is important to employ the γ-cyclodextrin derivativeand/or β-cyclodextrin derivative in combination with one or moreadditional solubilizers.

As such, the ophthalmic composition of the present invention includes atleast one solubilizing agent (i.e., solubilizer), but possibly two ormore solubilizing agents, in addition to cyclodextrin. The additionalsolubilizing agents can include surfactants such as castor oil,polysorbate or others. Preferably, the additional solubilizing agent[s]includes one or more polymers. One preferred polymer for aiding insolubilizing the olopatadine is lactam polymer. Another preferredpolymer for aiding in solubilizing the olopatadine is polyether.

As used herein, the phrase “lactam polymer” refers to any polymer formedfrom more than one lactam monomer. The lactam polymer is typicallypresent in the composition at a concentration that is at least 1.0% w/v,more typically at least 3.0% w/v and even more typically at least 3.7%w/v, but is typically no greater than 8.0% w/v, typically no greaterthan 5.0% w/v and is typically no greater than 4.3% w/v.Polyvinylpyrrolidone (PVP) is the most preferred lactam polymer and canbe the only or substantially the only lactam polymer. Thus, in apreferred embodiment, the lactam polymer consists or consistsessentially of only PVP. The average molecular weight of the lactampolymer, particularly when it is PVP, is at least 20,000, more typicallyat least 46,000 and even more typically at least 54,000 but is typicallyno greater than 90,000, more typically no greater than 70,000 and stillmore typically no greater than 62,000. One preferred PVP is sold underthe tradenames PLASDONE® K29/32 or K30, which have an average molecularweight of approximately 50,000 and are commercially available fromASHLAND SPECIALTY INGREDIENTS, headquartered in Wayne, N.J., USA.

The polyether can aid in the solubility of olopatadine in thecomposition and/or can provide tonicity to the composition (i.e., act asa tonicity agent). The polyether is typically present in the compositionat a concentration that is at least 1.0% w/v, more typically at least3.0% w/v and even more typically at least 3.7% w/v, but is typically nogreater than 8.0% w/v, typically no greater than 5.0% w/v and istypically no greater than 4.3% w/v. Polyethylene glycol (PEG) is themost preferred polyether and can be the only or substantially the onlypolyether polymer. Thus in a preferred embodiment, the polyetherconsists or consist essentially of only PEG. The average molecularweight of the PEG will typically depend upon the particular solubilityand particular tonicity desired for the composition. In a preferredembodiment, the average molecular weight of the polyether, particularlywhen it is PEG, is at least 200, more typically at least 320 and evenmore typically at least 380 but is typically no greater than 800, moretypically no greater than 580 and still more typically no greater than420. One preferred PEG is PEG400.

It may also be desirable for the ophthalmic composition of the presentinvention to include a viscosity enhancing agent in order to enhanceresidence time of the composition upon the cornea when the compositionis topically administered. Examples of potentially suitable viscosityenhancing agent include, without limitation, carboxyvinyl polymer,galactomannan, hyaluronic acid, cellulosic polymer, any combinationthereof or the like. In a preferred embodiment, the ophthalmiccomposition includes hydroxyethyl cellulose (HEC), hydroxylpropylmethylcellulose (HPMC) or both. One preferred HEC is sold under the tradenameNASTROSOL® 250HX, which is commercially available from HerculesIncorporated, Aqualon Division, Argyle, Tex. One preferred HPMC is soldunder the tradename E4M 2910 and is commercially available from DowChemical, Midland, Mich.

The amounts and molecular weights of HPMC and/or HEC used in thecomposition will depend upon the viscosity, osmolality and otherattributes to be achieved for the composition. As used herein, viscosityis measured by a Brookfield viscometer (LVDVI+, CP-42, 12 RPM and atemperature of 25° C.). In a preferred embodiment, the viscosity of thecomposition is at least 2.0 centipoise (cps), more typically at least 15cps, even more typically at least 21 cps and even possibly at least 27cps, but is typically no greater than 65 cps, typically no greater than40 cps, more typically nor greater than 33 cps and even possibly nogreater than 30 cps. Advantageously, and as further discussed below,viscosity within these ranges has been discovered to be more desirablefor producing desired droplet sizes when the composition of the presentinvention is topically delivered from an eye dropper.

The preferred average molecular weight of HEC, when used, is typicallyin the range of 90,000 to 1,300,000 (e.g., approximately 1,000,000). Thepreferred average molecular weight of HPMC is typically in the range of10,000 to 1,500,000 and more typically in the range of 189,000 to688,000).

When HPMC is used alone, it is typically present in composition at aconcentration that is at least 0.15% w/v, more typically at least 0.3%w/v and even more typically at least 0.5% w/v, but is typically nogreater than 1.5% w/v, typically no greater than 1.0% w/v and istypically no greater than 0.7% w/v. When HEC is used alone, it istypically present in the composition at a concentration that is at least0.1% w/v, more typically at least 0.25% w/v and even more typically atleast 0.45% w/v, but is typically no greater than 1.4% w/v, typically nogreater than 0.9% w/v and is typically no greater than 0.65% w/v.Advantageously, when HPMC and HEC are used to together, they may producea synergistic viscosity effect which allows the use of lowconcentrations of these excipients to produce the desired viscosity ofthe compositions. When HPMC and HEC are used in combination, HPMC istypically present in composition at a concentration that is at least0.05% w/v, more typically at least 0.1% w/v and even more typically atleast 0.2% w/v, but is typically no greater than 1.0% w/v, typically nogreater than 0.55% w/v and is typically no greater than 0.4% w/v. WhenHPMC and HEC are used in combination, HEC is typically present incomposition at a concentration that is at least 0.02% w/v, moretypically at least 0.06% w/v and even more typically at least 0.09% w/v,but is typically no greater than 0.6% w/v, typically no greater than0.3% w/v and is typically no greater than 0.17% w/v. Notably, in atleast some embodiments of the present invention, HPMC is a preferredviscosity enhancing agent since, as the data present below shows, it canalso aid in solubilizing the olopatadine.

The composition can also include buffering agents and/or tonicityagents. Suitable tonicity-adjusting agents and/or buffering agentsinclude, but are not limited to, mannitol, sodium chloride, glycerin,sorbitol, phosphates, borates, acetates and the like.

Borate is a highly preferred buffering agent and will typically beincluded in the composition of the present invention. As used herein,the term “borate” shall refer to boric acid, salts of boric acid, boratederivatives and other pharmaceutically acceptable borates, orcombinations thereof. Most suitable are: boric acid, sodium borate,potassium borate, calcium borate, magnesium borate, manganese borate,and other such borate salts. Typically, when used, the borate is atleast about 0.05 w/v %, more typically at least about 0.18 w/v % andeven possibly at least about 0.27 w/v % of the ophthalmic compositionand is typically less than about 1.0 w/v %, more typically less thanabout 0.75 w/v % and still more typically less than about 0.4 w/v %, andeven possibly less than about 0.35 w/v % of the ophthalmic composition.

The composition of the present invention can also include polyol. Asused herein, the term “polyol” includes any compound having at least onehydroxyl group on each of two adjacent carbon atoms that are not intrans configuration relative to each other. The polyol can be linear orcyclic, substituted or unsubstituted, or mixtures thereof, so long asthe resultant complex is water soluble and pharmaceutically acceptable.Examples of such compounds include: sugars, sugar alcohols, sugar acidsand uronic acids. Preferred polyols are sugars, sugar alcohols and sugaracids, including, but not limited to: mannitol, glycerin, xylitol,sorbitol and propylene glycol. It is contemplated that the polyol may becomprised of two or more different polyols.

When both borate and polyol are present in the composition, boratetypically interacts with polyol, such as glycerol, propylene glycol,sorbitol and mannitol, or any combination thereof to form borate polyolcomplexes. The type and ratio of such complexes depends on the number ofOH groups of a polyol on adjacent carbon atoms that are not in transconfiguration relative to each other. It shall be understood thatweight/volume percentages of the ingredients polyol and borate includethose amounts whether as part of a complex or not. Advantageously, theborate and polyol can act as buffers and/or tonicity agents and can alsoaid in enhancing preservation efficacy of the composition.

In a preferred embodiment of the invention, the composition includespropylene glycol, glycerine or both. It has been found thatγ-cyclodextrin derivatives and/or β-cyclodextrin derivatives tend toinhibit preservation efficacy within the formulations of the presentinvention, however, propylene glycol in the presence of borate appearsto significantly limit this inhibition. Moreover, it has been found thatglycerine often acts in a manner very similar to propylene glycol whenused for aiding preservation. When used, propylene glycol, glycerine ora combination thereof is typically present in the composition at aconcentration that is at least 0.4 w/v %, more typically at least 0.65w/v % and even possibly at least 0.85 w/v % but is typically no greaterthan 5.0 w/v %, more typically no greater than 2.2 w/v % and even moretypically no greater than 1.7 w/v %.

In a same or alternative preferred embodiment of the invention, thecomposition includes mannitol, sorbitol or both. Mannitol may also aidpreservation of the composition of the present invention when used inthe presence of borate. Moreover, it has been found that sorbitol oftenacts in a manner very similar to mannitol when used for aidingpreservation. When used, mannitol, sorbitol or a combination thereof istypically present in the composition at a concentration that is at least0.05 w/v %, more typically at least 0.2 w/v % and even possibly at least0.4 w/v % but is typically no greater than 3.0 w/v %, more typically nogreater than 1.0 w/v % and even more typically no greater than 0.5 w/v%.

The composition of the present invention typically includes apreservative. Potential preservatives include, without limitation,hydrogen peroxide, benzalkonium chloride (BAK), polymeric quaternaryammonium compound (PQAM), biquanides, sorbic acid, chlorohexidine orothers. Of these, benzalkonium chloride and polymeric quaternaryammonium compound such as polyquaternium-1 have proven quite desirable.

The polymeric quaternary ammonium compounds useful in the compositionsof the present invention are those which have an antimicrobial effectand which are ophthalmically acceptable. Preferred compounds of thistype are described in U.S. Pat. Nos. 3,931,319; 4,027,020; 4,407,791;4,525,346; 4,836,986; 5,037,647 and 5,300,287; and PCT application WO91/09523 (Dziabo et al.). The most preferred polymeric ammonium compoundis polyquaternium-1, otherwise known as POLYQUAD® with a number averagemolecular weight between 2,000 to 30,000. Preferably, the number averagemolecular weight is between 3,000 to 14,000.

When used, the polymeric quaternary ammonium compound is generally usedin the composition of the present invention in an amount that is greaterthan about 0.00001 w/v %, more typically greater than about 0.0003 w/v %and even more typically greater than about 0.0007 w/v % of theophthalmic composition. Moreover, the polymeric quaternary ammoniumcompound is generally used in the composition of the present inventionin an amount that is less than about 0.01 w/v %, more typically lessthan about 0.007 w/v %, even more typically less than 0.003 w/v %, stillmore typically less than 0.0022 w/v % and even possibly less than about0.0015 w/v % of the ophthalmic composition.

BAK is generally used in the composition of the present invention in anamount that is greater than about 0.001 w/v %, more typically greaterthan about 0.003 w/v % and even more typically greater than about 0.007w/v % of the ophthalmic composition. Moreover, BAK is generally used inthe composition of the present invention in an amount that is less thanabout 0.1 w/v %, more typically less than about 0.03 w/v % and even moretypically less than about 0.020 or 0.015 w/v % of the ophthalmiccomposition.

It is also contemplated that the composition of the present inventionmay benefit from the use of two different polyols, borate and apreservative (e.g., BAK or polymeric quaternary ammonium compound) toprovide enhanced preservations efficacy. Examples of such systems aredisclosed in U.S. Patent Publication Nos. 2009/0232763 and 2010/0324031,which are expressly incorporated herein in their entirety for allpurposes.

Notably, it has been found that polymeric ammonium compound isparticularly desirable for preserving compositions containing SAE-β-CDwhile BAK is particularly desirable for preserving compositionscontaining hydroxypropyl beta or gamma cyclodextrin derivatives. It hasalso been found that filtration (e.g., micron filtration) of thepreservative followed by aseptic addition of the preservative to thesterile composition can aid preservation efficacy.

It is contemplated that the composition of the present invention caninclude a variety of additional ingredients. Such ingredients include,without limitation, additional therapeutic agents, additional oralternative antimicrobial agents, suspension agents, surfactants,additional or alternative tonicity agents, additional or alternativebuffering agents, anti-oxidants, additional or alternativeviscosity-modifying agents, chelating agents any combinations thereof orthe like.

The compositions of the present invention will generally be formulatedas sterile aqueous solutions. The compositions of the present inventionare also formulated so as to be compatible with the eye and/or othertissues to be treated with the compositions. The ophthalmic compositionsintended for direct application to the eye will be formulated so as tohave a pH and tonicity that are compatible with the eye. It is alsocontemplated that the compositions can be suspensions or other types ofsolutions.

The composition of the present invention will typically have a pH in therange of 4 to 9, preferably 5.5 to 8.5, and most preferably 5.5 to 8.0.Particularly desired pH ranges are 6.0 to 7.8 and more specifically 6.4to 7.2. The compositions will have an osmolality of 200 to 400 or 450milliosmoles per kilogram (mOsm/kg), more preferably 240 to 360 mOsm/kg.

It is generally preferred that the composition of the present inventionbe provided in an eye dropper that is configured to dispense thecomposition as eyedrops topically to the cornea of the eye. However,desired size of a single eyedrop (i.e., droplet size) for the ophthalmiccomposition can be difficult to accomplish. It has been discovered thatthe cyclodextrin in the composition imparts a relatively high surfaceenergy to the composition. In turn, droplet size tends to be relativelyhigh. It has been discovered, however, that by dispensing dropletsthrough a relatively small orifice and/or by maintaining the viscosityof the composition within the ranges discussed above, desired dropletsize can be achieved. Desired droplet size is typically at least 10 moretypically at least 18 μl and even more typically at least 23 μl, but istypically no greater than 60 μl, typically no greater than 45 μl and istypically no greater than 33 μl. Advantageously, this droplet size forthe composition with the concentrations of olopatadine specified hereinallows an individual to dispense one droplet per eye once a day andreceive relief from symptoms of ocular allergic conjunctivitisgenerally, but particularly receive relief from late phase symptomsocular allergic conjunctivitis.

In a preferred embodiment, the composition of the present invention is amulti-dose ophthalmic compositions that have sufficient antimicrobialactivity to allow the compositions to satisfy the USP preservativeefficacy requirements, as well as other preservative efficacy standardsfor aqueous pharmaceutical compositions.

The preservative efficacy standards for multi-dose ophthalmic solutionsin the U.S. and other countries/regions are set forth in the followingtable:

Presevative Efficacy Test (“PET”) Criteria (Log Order Reduction ofMicrobial Inoculum Over Time Bacteria Fungi USP 27 A reduction of 1 log(90%), The compositions must by day 7; 3 logs (99.9%) by demonstrateover the entire day 14; and no increase test period, which means noafter day 14 increases of 0.5 logs or greater, relative to the initialinoculum Japan 3 logs by 14 days; and no No increase from initialincrease from day 14 count at 14 and 28 days through day 28 Ph. Areduction of 2 logs (99%) A reduction of 2 logs (99%) Eur. A¹ by 6hours; 3 logs by 24 by 7 days, and no increase hours; and no recoverythereafter after 28 days Ph. A reduction of 1 log at 24 A reduction of 1log (90%) Eur. B hours; 3 logs by day 7; and by day 14, and no increaseno increase thereafter thereafter FDA/ A reduction of 3 logs from Noincrease higher than the ISO initial challenge at day 14; initial valueat day 14, and 14730 and a reduction of 3 logs no increase higher thanthe from rechallenge day 14 rechallenge count through day 28 ¹There aretwo preservative efficacy standards in the European Pharmacopoeia ‘ “A”and “B”.

The standards identified above for the USP 27 are substantiallyidentical to the requirements set forth in prior editions of the USP,particularly USP 24, USP 25 and USP 26.

Advantages and Problems Overcome

The olopatadine ophthalmic composition of the present invention canprovide multiple advantages over the olopatadine compositions that camebefore it. The composition disclosed herein provides an aqueousophthalmic composition having a relatively high concentration ofolopatadine that provides enhanced relief from late phase allergicconjunctivitis and early phase allergic conjunctivitis. Surprisingly andadvantageously, preferred compositions of the present invention, asshown in FIGS. 1 through 5 and tables K through O, showed improvedreduction in early phase redness, in late phase redness and in latephase itching. It is surprising that the enhanced concentration ofolopatadine showed such significant reduction in late phase symptoms. Itis even more surprising that the enhanced concentration of olopatadineshowed enhanced reduction of early phase redness since it was generallybelieved that itching and redness would show similar responses todifferent concentrations of olopatadine.

Further, the composition can solubilize the relatively highconcentration of olopatadine in solution form suitable as an eyedropwhere other formulations have failed. Further yet, the composition cansolubilize the higher concentrations of olopatadine while maintainingefficacy in treatment of the symptoms of allergic conjunctivitis whereother efforts to develop such a solution have failed. Still further, thecompositions can, when in multi-dose form, pass preservation efficacystandards where other compositions have failed.

As an additional advantage, it has been discovered that, for theparticular composition of the present invention, composition containingHP-γ-CD have unexpectedly been found to be more susceptible topreservation. It has also unexpectedly been found to have solubilitycharacteristics similar to the other beta cyclodextrin derivativediscussed herein. This discovery has been particularly advantageous inproviding a composition that is capable of solubilizing relatively highconcentrations of olopatadine, capable of being stable for extended timeperiods and capable of robust preservation relative to both European andUnited States preservation efficacy standards.

It is still further advantageous that the cyclodextrin does not appearto interfere with the efficacy of the olopatadine. In particular,cyclodextrins have been found to entrap other drugs in a manner thatdoes not allow those drugs to later release and show efficacy. However,this was not the case for olopatadine and was particularly not the casefor HP-γ-CD.

Applicants specifically incorporate the entire contents of all citedreferences in this disclosure. Further, when an amount, concentration,or other value or parameter is given as either a range, preferred range,or a list of upper preferable values and lower preferable values, thisis to be understood as specifically disclosing all ranges formed fromany pair of any upper range limit or preferred value and any lower rangelimit or preferred value, regardless of whether ranges are separatelydisclosed. Where a range of numerical values is recited herein, unlessotherwise stated, the range is intended to include the endpointsthereof, and all integers and fractions within the range. It is notintended that the scope of the invention be limited to the specificvalues recited when defining a range.

Other embodiments of the present invention will be apparent to thoseskilled in the art from consideration of the present specification andpractice of the present invention disclosed herein. It is intended thatthe present specification and examples be considered as exemplary onlywith a true scope and spirit of the invention being indicated by thefollowing claims and equivalents thereof.

Table A below provides a listing of exemplary ingredients suitable foran exemplary preferred formulation of the ophthalmic composition of thepresent invention and a desired weight/volume percentage for thoseingredients. It shall be understood that the following Table A isexemplary and that certain ingredients may be added or removed from theTable and concentrations of certain ingredients may be changed while theformulation can remain within the scope of the present invention, unlessotherwise specifically stated.

TABLE A Ingredient w/v percent Olopatadine (Olopatadine HCl) 0.7Polyether (PEG) 4.0 Lactam Polymer (PVP) 4.0 Viscosity Agent (HEC) 0.1(if used w/HPMC or other viscosity agent) 0.3 (if used w/o HPMC or otherviscosity agent) Viscosity Agent (HPMC) 0.15 (if used w/HEC or otherviscosity agent) 0.35 (if used w/o HEC or other viscosity agent)Chelating agent (Disodium  0.005 EDTA) Borate (Boric Acid) 0.3γ-cyclodextrin derivative and 1.0 for SAE-β-CD or 1.5 or β-cyclodextrinderivative HP-β-CD or 1.5 HP-γ- CD Polyol (Mannitol) 0.3 Polyol(Propylene Glycol) 1.0 Tonicity Agent (Sodium  0.35 Chloride)Preservative 0.01 for BAK or 0.0015 PQAM pH adjusting agents (NaOH orHCl) sufficient to achieve pH = 7.0 purified water Q.S. 100

The following examples are presented to further illustrate selectedembodiments of the present invention. The formulations shown in theexamples were prepared using procedures that are well-known to personsof ordinary skill in the field of ophthalmic pharmaceuticalcompositions.

EXAMPLES Preparatory Example 1

Ingredients Composition (w/w) Olopatadine hydrochloride 0.77 g Hydroxypropyl-β-Cyclodextrin(HP-β-CD) 1.5 g PEG400(Polyethylene glycol400) 4.0 g PVP(Polyvinylpyrrolidone K30) 4.0 g HPMC (Methocel E4mPremium) 0.6 g HEC(Natrosol 250HX) 0.3 g Disodium EDTA 0.01 g  Mannitol0.6 g Boric Acid 0.3 g Benzalkonium Chloride 0.01 g  HCl/NaOH q.s. to pH7.0 Purified water q.s. to 100 g

In a clean suitable and tared glass bottle, add and dissolve HPMC withan amount of purified water at 90-95° C. equivalent to about 15% of therequired batch size. Mix by stirring until homogenization. Bring to the35% of the final weight with purified water and mix by stirring withpropeller until complete dispersion. Add HEC and mix by stirring untilhomogenization. Steam sterilize the solution (122° C./20 min) and coolafterwards (Part A). In a separate vessel with a stir bar, add an amountof purified water equivalent to about 40% of the required batch size.Add and dissolve batch quantities of weighed PEG400, PVP, HP-β-CD,Olopatadine HCl, Boric Acid, Mannitol, EDTA and BAC, allowing eachcomponent to dissolve before adding the next component. Check the pH andadjust to 7.0±0.1 with the required amount of NaOH 2N (Part B). In alaminar flow hood (sterile conditions), filter the solution Part B intothe glass bottle containing the autoclaved fraction (Part A), using GVPVDF membrane, 0.22 μm filter unit and stir until homogenization. Mix bystirring with propeller for 15 min. Check the pH and adjust to 7.0±0.1with the required amount of NaOH 1N/HCl 1N, if necessary. Bring to finalweight with sterile purified water and stir until homogenization.

Preparatory Example 2

Ingredients Composition (w/w) Olopatadine hydrochloride 0.77 g Hydroxypropyl-β-Cyclodextrin (HP-β-CD) 1.5 g PVP(PolyvinylpyrrolidoneK30) 4.0 g PEG400(Polyethylene glycol 400) 4.0 g HPMC (Methocel E4mPremium) 0.2 g HEC(Natrosol 250HX) 0.125 g  Disodium EDTA 0.01 g  BoricAcid 0.3 g Benzalkonium Chloride 0.01 or 0.015 g NaOH 1N 0.83 ml HCl 1N0.58 ml HCl/NaOH q.s. to pH 7.0 Purified water q.s. to 100 g

In a clean suitable and tared glass bottle, add and dissolve HPMC withan amount of purified water at 90-95° C. equivalent to about 15% of therequired batch size. Mix by stirring until homogenization. Bring to the30% of the final weight with purified water and mix by stirring withpropeller until complete dispersion. Add HEC and mix by stirring untilhomogenization (Part A). In a clean beaker with stir bar, weigh anamount of purified water equivalent to about 40% of the required batchsize. Heat and maintain this water around 70-75° C. Add NaOH 1N and mixby moderate stirring. Add PVP and dissolve under agitation during 20minutes. Add HCl 1N, mix and quickly cool down to 30-40° C. Add anddissolve batch quantities of PEG400, HP-β-CD, Olopatadine HCl, BoricAcid, EDTA and BAC, allowing each component to dissolve before addingthe next component. Check the pH of the solution and adjust to 6.8±0.1with the required amount of NaOH 2N (Part B). Transfer Part B to Part Aand stir the batch until it is homogenous. Bring to the 85% of the finalweight with purified water and stir until homogenization. Steamsterilize the solution (122° C./20 min) and cool afterwards. In alaminar flow hood (sterile conditions), check the pH and adjust to7.0±0.1 with the required amount of NaOH 1N/HCl 1N, if necessary. Bringto final weight with sterile purified water and stir untilhomogenization.

Formulary Examples A through I in Table B below

Formulary Examples A through I show the solubility of olopatadine indifferent formulations.

Ingredients A B C D E PEG 400 4 4 4 4 3.8 Dibasic Sodium 0.15 — — — 0.5Phosphate, anhydrous Hydroxypropyl-β- — 1.5 1.5 1.5 1 CyclodextrinSulfobutyl ether β 2 — — — — Cyclodextrin PVP K29/32 5 5 3 4 1.5Polysorbate 80 0.1 — — — — Tyloxapol — — — — — Natrosol 250HX 0.3 0.30.3 0.3 — HPMC 2910 0.6 0.6 0.6 0.6 — Boric Acid — 0.3 0.3 0.3 — SodiumChloride 0.15 — — — — Mannitol — 0.6 0.6 0.6 — Benzalkonium Chloride0.01 0.01 0.01 0.01 0.01 Disodium EDTA 0.01 0.01 0.01 0.01 0.01 SodiumHydroxide/Hydrochloric Acid quantity sufficient to achieve pH of 7.4Purified water quantity sufficient to 100% Olopatadine Solubility (%)1.064 0.901 0.725 0.811 0.461 Ingredients F G H I PEG 400 6 6 6 6Dibasic Sodium 0.5 0.5 0.5 0.5 Phosphate, anhydrous Hydroxypropyl-β- — 11 1 Cyclodextrin Sulfobutyl ether β — — — — Cyclodextrin PVP K29/32 1.5— 1.5 1.5 Polysorbate 80 — — — — Tyloxapol — — — 0.05 Natrosol 250HX — —— — HPMC 2910 — — — — Boric Acid — — — — Sodium Chloride — — — —Mannitol — — — — Benzalkonium Chloride 0.01 0.01 0.01 0.01 Disodium EDTA0.01 0.01 0.01 0.01 Sodium Hydroxide/Hydrochloric Acid quantitysufficient to achieve pH of 7.4 Purified water quantity sufficient to100% Olopatadine Solubility (%) 0.352 0.450 0.513 0.494

As can be seen, cyclodextrin can significantly enhance the solubility ofolopatadine in aqueous solution. Moreover, it will be understood thatthe formulations of lower solubility, particularly those withoutcyclodextrin, will also typically exhibit worse solubilitycharacteristics over time and tend to form precipitates.

Formulary Example J through M in Table C below

Formulary Examples J through M show the preservation efficacy ofolopatadine containing formulations both with and withoutβ-cyclodextrin.

Ingredients J K L M Olopatadine HCL 0.77 0.77 0.77 0.77 PEG 400 — 4 — —Sodium Pyruvate — — — Dibasic Sodium Phosphate, 0.15 0.15 0.15 0.1anhydrous Purified Guar — — — 0.17 Hydroxypropyl-β-Cyclodextrin 1.5 — —5 PVP K30 2 3 3 — Tyloxapol — — 0.2 — Polysorbate 80 — 0.1 — — Natrosol250HX 0.3 0.3 — HPMC 2910 — 0.6 0.6 — Boric Acid — — — 0.17 SodiumBorate, decahydrate — — — 0.5 Propylene Glycol — — — — Sodium Chloride —0.15 0.55 0.1 Mannitol 2.5 — — — Sorbitol — — — 1 Sodium Citrate,dihydrate — — — 0.35 Benzalkonium Chloride 0.01 0.01 0.01 0.01Polyquaternium-1 — — — — Disodium EDTA 0.01 0.01 0.01 — SodiumHydroxide/ q.s. to q.s. to q.s. to q.s. to Hydrochloric Acid pH 7.0 pH7.0 pH 7.0 pH 7.0 Purified water q.s. to q.s. to q.s. to q.s. to 100%100% 100% 100% PET Log₁₀ Unit Reduction S. aureus 0.1/1.9/ 5.0/5.0/1.5/5.0/ 0.0/0.0/ 6 h/24 h/7 d/14 d/28 d 5.0/5.0/ 5.0/5.0/ 5.0/5.0/0.9/3.3/ 5.0 5.0 5.0 5.0 P. aerugin 4.9/4.9/ 4.9/4.9/ 4.9/4.9/ 0.3/0.5/6 h/24 h/7 d/14 d/28 d 4.9/4.9/ 4.9/4.9/ 4.9/4.9/ 0.0/0.0/ 4.9 4.9 4.90.5 E. coli 2.8/4.9/ 4.9/4.9/ 4.9/4.9/ 0.1/0.2/ 6 h/24 h/7 d/14 d/28 d4.9/4.9/ 4.9/4.9/ 4.9/4.9/ 1.4/3.3/ 4.9 4.9 4.9 5.0 C. albican 4.3/5.1/5.1/5.1/ 2.5/5.1/ 0.7/2.7/ 7 d/14 d/28 d 5.1/4.1/ 5.1/5.1/ 5.1 3.2 4.15.1 A. niger 0.8/0.9/ 2.1/4.2/ 0.7/1.7/ 1.2/1.1/ 7 d/14 d/28 d 1.3 4.92.3 1.5

As can be seen, cyclodextrin derivatives can significantly inhibit theability of a preservative to provide desired preservation to an aqueousformulation.

As an added advantage, it has also been discovered that HPMC can aid insolubilizing olopatadine. This effect is shown in Table D below.

TABLE D % PVP % SBE- % PEG Concentration K29/32 CD 400 % HPMC (mg/mL)Final pH 4 1.5 4 — 6.13 6.97 4 2.0 4 — 6.74 6.97 4 2.2 4 — 6.97 7.01 42.3 4 — 7.16 7.02 4 2.5 4 — 7.34 6.98 4 1.5 4 0.6 7.46 6.96 4 2.0 4 0.68.11 7.06 4 2.2 4 0.6 8.62 7.02 4 2.3 4 0.6 8.66 7.01 4 2.5 4 0.6 9.047.04

Table E below presents several formulations (N through Q) that cansolubilize a high concentration of olopatadine using PVP in combinationwith a relatively low amount of HP-β-CD and that show desirablepreservation using a combination of BAK and Boric Acid. Notably, PEG andHPMC are also believed to be aiding in the solubility of olopatadine.

TABLE E Ingredients N O P Q Olopatadine HCL 0.77 0.77 0.77 0.77 PEG 4004 4 4 4 Hydroxypropyl-β- 1.5 1.5 1.5 1.5 Cyclodextrin PVP K29/32 4 4 4 4Natrosol 250HX 0.3 0.3 0.3 0.125 HPMC 2910 0.6 0.6 0.6 0.2 Boric Acid0.3 0.3 0.3 0.3 Disodium EDTA 0.01 0.01 0.01 0.01 Benzalkonium Chloride0.01 0.01 0.01 0.01 Polyquaternium-1 — — — — Sodium Hydroxide/ q.s. toq.s. to q.s. to q.s. to Hydrochloric Acid pH 7 pH 7 pH 7 pH 7 Purifiedwater q.s. to q.s. to q.s. to q.s. to 100% 100% 100% 100% PET ResultLog₁₀ Unit Reduction S. aureus 0.4/3.6/ 0.2/1.4/ 0.3/2.9/ 0.4/3.2/ 6h/24 h/7 d/14 d/28 d 4.9/4.9/ 5.0/5.0/ 4.9/4.9/ 5.0/5.0/ 4.9 5.0 4.9 5.0P. aerugin 5.0/5.0/ 5.1/5.1/ 5.0/5.0/ 5.2/5.2/ 6 h/24 h/7 d/14 d/28 d5.0/5.0/ 5.1/5.1/ 5.0/5.0/ 5.2/5.2/ 5.0 5.1 5.0 5.2 E. coli 4.9/4.9/2.7/5.1/ 2.1/5.1/ 2.3/5.1/ 6 h/24 h/7 d/14 d/28 d 4.9/4.9/ 5.1/5.1/5.1/5.1/ 5.1/5.1/ 4.9 5.1 5.1 5.1 C. albican 4.9/4.9/ 2.5/4.8/ 1.6/4.1/2.4/4.6/ 7 d/14 d/28 d 4.9 4.8 5.0 4.6 A. niger 3.8/5.2/ 3.6/5.1/4.3/5.2/ 3.9/4.7/ 7 d/14 d/28 d 5.2 5.1 5.2 5.2

Tables F and G below show the difficulty associated with preservation offormulations (R through X) containing SBE-β-CD.

TABLE F R S T U Ingredient Olopatadine HCl 0.77 0.77 0.77 0.77Sulfobutylether-β- 0.75 0.75 0.75 0.75 Cyclodextrin PVP K29/32 4 4 4 4PEG 400 2 2 2 2 Natrosol 250HX — — — — HPMC 2910 0.6 0.6 0.6 0.6 BoricAcid 0.6 0.3 0.3 0.3 Mannitol — — 0.2 — Disodium EDTA — 0.01 0.01 0.01Polyquaternium-1 0.001 — — — BAC — 0.02 0.02 — Benzododecinium — — — —Bromide Sorbic Acid — — — 0.2 Thimerosal — — — — Chlorhexidine — — — —Digluconate NaOH/HCl q.s. to q.s. to q.s. to q.s. to pH 7.0 pH 7.0 pH7.0 pH 6.0 Purified water q.s. to q.s. to q.s. to q.s. to 100 100 100100 PET RESULTS S. aureus 1.8/2.8/ 0.0/0.5/ 0.0/0.4/ 0.1/0.1/ 6 h/24 h/7d/14 d/28 d 5.0/5.4/ 4.7/ 4.7/ 4.7/ P. aerugin 0.6/0.8/ 5.0/5.0/5.0/5.0/ 5.0/5.0/ 6 h/24 h/7 d/14 d/28 d 5.4/5.4/ 5.0/ 5.0/ 5.0/ E. coli1.2/3.2/ 1.4/3.1/ 1.7/3.2/ 0.2/0.3/ 6 h/24 h/7 d/14 d/28 d 5.4/5.4/ 5.1/5.1/ 5.1/ C. albicans 0.3/1.5/ 0.7/ 0.6 0.1/ 7 d/14 d/28 d A. niger0.7/0.7/ 2.1/ 1.2 1.1/ 7 d/14 d/28 d

TABLE G V W X Ingredients Olopatadine HCl 0.77 0.77 0.77Sulfobutylether-β- 0.75 0.75 0.75 Cyclodextrin PVP K29/32 4 4 4 PEG 4002 2 2 Natrosol 250HX — — — HPMC 2910 0.6 0.6 0.6 Boric Acid 0.3 0.3 0.3Mannitol — — — Disodium EDTA 0.01 0.01 0.01 Polyquaternium-1 — — — BAC —— — Benzododecinium Bromide 0.02 — — Sorbic Acid — — — Thimerosal — 0.01— Chlorhexidine Digluconate — — 0.01 NaOH/HCl q.s. to q.s. to q.s. to pH7.0 pH 7.0 pH 7.0 Purified water q.s. to q.s. to q.s. to 100 100 100 PETRESULTS S. aureus 0.0/0.1/4.7/ 0.0/0.0/4.7/ 0.0/0.4/4.7/ 6 h/24 h/7 d/14d/28 d P. aerugin 5.0/5.0/5.0/ 5.0/5.0/5.0/ 5.0/5.0/5.0/ 6 h/24 h/7 d/14d/28 d E. coli 0.6/1.3/5.1/ 1.1/5.0/5.0/ 1.0/3.9/5.0/ 6 h/24 h/7 d/14d/28 d C. albicans 0.5/ 5.8/ 3.9/ 7 d/14 d/28 d A. niger 1.2/ 5.0/ 1.4 7d/14 d/28 d

Tables H and I show the achievement of significantly improvedpreservation of formulations (Y through II), which also containSBE-β-CD.

TABLE H AA BB CC DD Y Z +++ ++− +−+ −+− Ingredients Olopatadine HCl 0.770.77 0.77 0.77 0.77 0.77 Sulfobutylether- 1.5 1.5 1 1 1 0.75β-Cyclodextrin PVP K29/32 4 4 4 4 4 4 PEG 400 4 4 2 2 2 2 Natrosol 250HX0.3 0.3 — — — — HPMC 2910 0.6 0.6 0.6 0.6 0.6 0.6 Boric Acid 0.3 0.3 0.30.3 0.3 0.3 Mannitol 0.6 — — — — — Propylene glycol — 1 1 0.5 1 0.5Polyquaternium-1 0.001 0.001 0.002 0.002 0.001 0.002 Sodium Hydroxideand/or Hydrochloric acid Qs to pH 7.2 Purified Water Qs to 100 PET DATAS. aureus 0.9/1.7/4.9/ 1.2/1.6/4.9/ 1.6/2.2/4.7/ 1.6/2.4/4.7/1.8/2.0/4.7/ 2.1/2.9/5.05 6 h/24 h/7 4.9/4.9 4.9/4.9 4.7/4.7 4.7/4.74.7/4.7 .0/ d/14 d/28 d P. aerugin 3.4/4.9/4.9/ 0.3/1.4/5.2/0.0/1.0/4.6/ 0.2/1.2/5.1/ 0.1/1.0/5.1/ 0.6/1.5/5.45 6 h/24 h/7 4.9/4.95.2/5.2 5.1/5.1 5.1/5.1 5.1/5.1 .4/ d/14 d/28 d E. coli 1.9/4.2/4.9/1.0/2.7/5.2/ 0.3/1.6/4.8/ 1.7/4.8/4.8/ 0.3/1.2/4.8/ 2.2/4.9/5.45 6 h/24h/7 4.9/4.9 5.2/5.2 4.8/4.8 4.8/4.8 4.8/4.8 .4/ d/14 d/28 d C. albican0.1/0.4/0.4 0.9/1.1/2.1 1.2/2.5/ 1.0/2.2/ 0.8/2.3/ 0.9/2.7/ 7 d/14 d/28d A. niger 3.6/3.6/3.1 1.0/1.0/1.0 0.6/0.7/ 0.2/0.8/ 0.2/0.8/ 0.6/0.8/ 7d/14 d/28 d

TABLE I FID EE FF GG HH II −++ −−− +−− −−+ NA Olopatadine HCl 0.77 0.770.77 0.77 0.77 Sulfobutylether- 0.75 0.75 1 0.75 0.75 β-Cyclodextrin PVPK29/32 4 4 4 4 4 PEG 400 2 2 2 2 2 Natrosol 250HX — — — — — HPMC 29100.6 0.6 0.6 0.6 0.6 Boric Acid 0.3 0.3 0.3 0.3 0.6 Mannitol — — — — —Propylene glycol 1 0.5 0.5 1 — Polyquaternium-1 0.002 0.001 0.001 0.0010.001 Sodium Hydroxide and/or Hydrochloric acid Qs to pH 7.2 PurifiedWater Qs to 100 PET DATA S. aureus 2.0/3.1/4.7/ 0.7/1.2/4.7/1.5/1.8/4.7/ 2.0/2.9/5.05 1.8/2.8/5.05 6 h/24 h/7 d/14 d/28 d 4.7/4.74.7/4.7 4.7/4.7 .0/ .4/ P. aerugin 0.5/1.4/5.1/ 0.0/0.4/2.0/0.4/1.1/5.1/ 0.6/6.3/5.45 0.6/0.8/5.45 6 h/24 h/7 d/14 d/28 d 5.1/5.11.2/0.2 5.1/5.1 .4/ .4/ E. coli 1.6/4.6/4.8/ 0.0/0.0/0.00 0.2/0.8/4.8/2.4/5.2/5.45 1.2/3.2/5.45 6 h/24 h/7 d/14 d/28 d 4.8/4.8 .0/2.6 4.8/4.8.4/ .4/ C. albican 1.1/2.7/ 0.6/1.9/ 0.7/1.9/ 0.3/2.4/ 0.3/1.5/ 7 d/14d/28 d A. niger 0.7/0.8/ 0.7/0.9/ 0.7/0.8/ 0.7/0.8/ 0.7/0.7/ 7 d/14 d/28d

Table J illustrates that formula preservation can best be achieved usingHP-γ-CD. In particular, formulas JJ through TT in Table J exhibit robustpreservation relative to both European and United States preservationstandards. This is particularly surprising when the data in Table J iscompared with the data in Tables A, B and E since there is no readilyidentifiable reason that the formulations containing HP-γ-CD shouldexhibit greater preservation efficacy relative to the formulationscontaining HP-β-CD.

TABLE J Formula JJ KK LL MM NN OO Batch # 11-63920 11-63921 11-6390011-63901 11-63902 11-63922 Component Olopatadine 0.77 0.77 0.77 0.770.77 0.77 Hydrochloride HP-γ-CD 1.5 1.5 1.5 1.5 1.5 1.5 Povidone K29/324 4 4 4 4 4 PEG 400 4 4 4 4 4 4 HPMC 2910 E4M 0.4 0.4 0.4 0.4 0.4 0.4Boric acid 0.3 0.3 0.3 0.3 0.3 0.3 Mannitol 0.2 0.2 0.2 0.2 0.2 0.2Disodium EDTA — — — — — 0.005 Benzalkonium 0.015 0.0125 0.01 0.00750.005 0.015 Chloride Sodium Hydroxide and/or Hydrochloric acid Qs to pH7.2 Purified Water Qs to 100 PET DATA S. aureus 4.9/4.9/4.9/4.9/4.9/4.9/ 4.8/4.8/4.8/ 4.8/4.8/4.8/ 4.8/4.8/4.8/ 4.9/4.9/4.9/ 6 h/24h/7 4.9/4.9 4.9/4.9 4.8/4.8 4.8/4.8 4.8/4.8 4.9/4.9 d/14 d/28 d P.aeruginosa 4.9/4.9/4.9/ 4.9/4.9/4.9/ 4.9/4.8/4.9/ 4.9/4.9/4.9/4.9/4.9/4.9/ 4.9/4.9/4.9/ 6 h/24 h/7 4.9/4.9 4.9/4.9 4.9/4.9 4.9/4.94.9/4.9 4.9/4.9 d/14 d/28 d E. coli 5.0/5.0/5.0/ 2.6/5.0/5.0/1.1/3.0/4.9/ 0.9/1.8/4.9/ 0.4/1.2/4.9/ 5.0/5.0/5.0/ 6 h/24 h/7 5.0/5.05.0/5.0 4.9/4.9 4.9/4.9 4.9/4.9 5.0/5.0 d/14 d/28 d C. albican4.8/4.8/4.8 4.8/4.8/4.8 4.9/4.9/4.9 4.9/4.9/4.9 4.9/4.9/4.9 4.8/4.8/4.86 h/24 h/7 d/14 d/28 d A. niger 5.1/5.1/5.1 5.1/5.1/5.1 5.1/5.1/5.15.1/5.1/5.1 5.1/5.1/5.1 5.1/5.1/5.1 6 h/24 h/7 d/14 d/28 d Test ResultspH Initial 7.31 7.25 7.25 7.20 7.29 7.25 FID PP QQ RR SS TT Batch #11-63923 11-63899 11-63905 11-63908 11-64011 Component Olopatadine 0.770.77 0.77 0.77 0.77 Hydrochloride HP-γ-CD 1.5 1.5 1.5 1.5 1.5 PovidoneK29/32 4 4 4 4 4 PEG 400 4 4 4 4 4 HPMC 2910 E4M 0.4 0.4 0.4 0.4 0.4Boric acid 0.3 0.3 0.3 0.3 0.3 Mannitol 0.2 0.2 0.2 0.2 0.2 DisodiumEDTA 0.005 0.005 0.005 0.005 0.005 Benzalkonium 0.0125 0.01 0.0075 0.0050.01 Chloride Sodium Hydroxide and/or Hydrochloric acid Qs to pH 7.2Purified Water Qs to 100 PET DATA S. aureus 4.9/4.9/4.9/ 4.8/4.8/4.8/4.8/4.8/4.8/ 4.9/4.9/4.9/ 5.0/5.0/5.0/ 6 h/24 h/7 4.9/4.9 4.8/4.84.8/4.8 4.9/4.9 5.0/5.0 d/14 d/28 d P. aeruginosa 4.9/4.9/4.9/4.9/4.9/4.9/ 4.9/4.9/4.9/ 4.9/4.9/4.9/ 5.0/5.0/5.0/ 6 h/24 h/7 4.9/4.94.9/4.9 4.9/4.9 4.9/4.9 5.0/5.0 d/14 d/28 d E. coli 5.0/5.0/5.0/4.9/4.9/4.9/ 4.9/4.9/4.9/ 5.0/5.0/5.0/ 5.1/5.1/5.1/ 6 h/24 h/7 5.0/5.04.9/4.9 4.9/4.9 5.0/5.0 5.1/5.1 d/14 d/28 d C. albican 4.8/4.8/4.84.9/4.9/4.9 4.9/4.9/4.9 4.8/4.8/4.8 4.9/4.9/4.9 6 h/24 h/7 d/14 d/28 dA. niger 4.4/5.1/5.1 5.1/5.1/4.9 5.1/5.1/5.1 4.4/5.1/5.1 5.3/5.3/5.3 6h/24 h/7 d/14 d/28 d Test Results pH Initial 7.24 7.24 7.23 7.28 7.29

Tables K through O below corresponding to graphs in FIGS. 1 through 5,provide results from a conjunctival allergen challenge (CAC) study of ahigh concentration olopatadine composition as compared to a marketedlower concentration olopatadine composition (marketed as PATADAY® byAlcon Laboratories, Inc., a Novartis Company). The CAC study wasperformed according to a standard CAC model that instills allergen inthe eye (the challenge) and then makes determinations of ocular rednessand ocular itching at time points (determination times) after thechallenge. The CAC study was performed by ORA, Inc., Andover, Mass.,United States, 01810, which uses a model accepted by the food and drugadministration (FDA). It is noted that in tables K through O and FIGS. 1through 5, the references to 0.77% olopatadine are references toolopatadine HCL and actually represent 0.7% olopatadine as base and thereferences to 0.2% olopatadine are references to 0.22% olopatadine HCLand 0.2% olopatadine as base.

In the CAC model, each patient is dosed with drug or vehicle and exposedto allergen at specific challenge times. The challenge times for thestudy were 27 minutes, 16 hours and 24 hours after dosing. Thereafter,itching is determined at determination times of 3, 5 and 7 minutes afterchallenge times and redness is determined at determination times of 7,15 and 20 minutes after the challenge times. Therefore, patientsreceived three doses of drug or vehicle and each dose was followed by anallergen challenge and then the itching and redness determination aremade as discussed. Results from the determination times are provided inTables K through O and the graphs of FIGS. 1 through 5.

Redness scores are determined on a scale of 0 to 4 by visual observationand the patient is asked to rate their ocular itching on a scale of 0 to4 to attain itching scores and in each score 0 is the least and 4 isgreatest. The results of those determinations at those time points areprovided in Tables K through O and the graphs of FIGS. 1 through 5. Eachof Tables K through O provide a mean score (Mean), a standard deviation(Std) to that score, a number (N) of patients, a minimum (Min) scoredetermined for any of the patients, a maximum (Max) score determined forany of the patients and p-values for indications of statisticalsignificance with a p-value of less than 0.05 indicating statisticalsignificance.

Table K below provides data relative to mean conjunctival redness asdetermined by the conjunctival allergen challenge (CAC) study 27 minutesafter challenge and that data is provided as a graph in FIG. 1.

TABLE K Conjunctival Redness (Onset-of-Action CAC) By Time Overall MeanStd N Min Max p-value p-value  7 min Olopatadine 0.77% 0.8 0.7 63 0 3Olopatadine 0.2% 1.3 0.8 63 0 3 <.0001 <.0001 Vehicle 2.1 0.7 60 0 3<.0001 <.0001 15 min Olopatadine 0.77% 1.1 0.9 63 0 3 Olopatadine 0.2%1.9 0.8 63 0 3 <.0001 Vehicle 2.3 0.6 60 1 4 <.0001 20 min Olopatadine0.77% 1.1 0.8 63 0 3 Olopatadine 0.2% 1.9 0.8 63 0 3 <.0001 Vehicle 2.30.7 60 0 4 <.0001 Main Effect of Treatment p-value = <.0001 Treatment byTime Interaction p-value = 0.0036

As can be seen in Table K and FIG. 1, olopatadine at a concentration of0.7% (note that the 0.77% above is for olopatadine HCl and represents0.7% olopatadine) provides statistically significant (i.e., p<0.05)relief of redness at onset-of-action relative to both vehicle andolopatadine 0.2%. Further, olopatadine at a concentration of 0.7%provides more that a 1.0 unit difference relative to vehicle in reliefof redness. Olopatadine at this concentration is believed to be thefirst antihistamine/mast cell stabilizer to provide such a difference.This data is particularly surprising since, prior to this CAC study,there was no indication that a high concentrations olopatadinecomposition would provide any additional reduction in redness atonset-of-action.

Olopatadine's IC₅₀ value or half maximal inhibitory concentration (IC₅₀)for inhibition of human conjunctival mast cell degranulation is in the500 to 600 μM range. Olopatadine's binding affinity (Ki) value forhistamine binding to the H1 receptor is in the 30 to 50 nM range. Themolar concentration of olopatadine in a 0.1% solution of olopatadine isapproximately 2.5 mM. These values suggest that a 0.1% solution ofolopatadine should have more than a sufficient quantity of olopatadineto provide maximal inhibition of human conjunctival mast celldegranulation and maximal fully histamine binding.

In particular, for inhibition of mast cell degranulation, these valuesindicate that when a 0.1% solution of olopatadine is dosed onto the eye,there is exposure to 5 times the IC₅₀ value for mast cell degranulation(500 μM vs 2.5 mM). When a 0.2% olopatadine solution is dosed to theeye, the exposure increases from approximately 2.5 mM (for a 0.1%solution) to 5 mM or about 10 times excess drug for inhibition of mastcell degranulation. Because olopatadine does not have anyvasoconstrictive effect, which would typically reduce redness, thisinhibition of redness is believed to result from inhibition of therelease of the mast cell mediators brought about by the mast celldegranulation. As such, a 0.1% or 0.2% solution of olopatadine shouldprovide full inhibition of redness at onset of action since both ofthese solutions provide excess olopatadine for inhibiting mast celldegranulation.

Surprisingly, however, the data in Table K and FIG. 1 show that a 0.7%solution of olopatadine prevents redness even better than a 0.2%solution of olopatadine at onset of action. Even more surprising, itprovides a statistically significant difference in redness inhibitionrelative the 0.2% solution at onset of action.

In contrast to this surprising discovery relative to redness, a similarfinding was not made for itching (see Table KK below), which is believedto be avoided through histamine binding.

TABLE KK Ocular Itching (Onset-of-Action CAC) By Time Overall Mean Std NMin Max p-value p-value 3 min Olopatadine 0.77% 0.4 0.7 63 0 3Olopatadine 0.2% 0.4 0.6 63 0 3 0.8434 Vehicle 1.9 1.1 60 0 4 <.0001 5min Olopatadine 0.77% 0.6 0.8 63 0 3 Olopatadine 0.2% 0.7 0.7 63 0 30.5341 Vehicle 2.1 1.1 60 0 4 <.0001 7 min Olopatadine 0.77% 0.5 0.7 630 3 Olopatadine 0.2% 0.7 0.8 63 0 4 0.3667 0.5441 Vehicle 2.0 1.1 60 0 4<.0001 <.0001 Main Effect of Treatment p-value = <.0001 Treatment byTime Interaction p-value = 0.4025

The similarity in itching values for olopatadine 0.7% and olopatadine0.2% for itching at onset of action are to be expected since 0.2%olopatadine and 0.7% olopatadine both provide enough olopatadine toprovide maximal inhibition of itching at onset of action. Thus, theabove discussed finding relative to redness at onset of action is quiteunique.

Table L below provides data relative to mean conjunctival rednessdetermined by the CAC study 16 hours after challenge and that data isprovided as a graph in FIG. 2.

TABLE L Conjunctival Redness (16 hrs Duration CAC) By Time Overall MeanStd N Min Max p-value p-value  7 min Olopatadine 0.77% 1.3 0.8 65 0 3Olopatadine 0.2% 1.6 0.7 65 1 3 0.0123 0.0056 Vehicle 1.8 0.8 65 1 3<.0001 0.0001 15 min Olopatadine 0.77% 1.5 0.8 65 0 4 Olopatadine 0.2%1.9 0.7 65 1 4 0.0061 Vehicle 1.9 0.8 65 1 4 0.0013 20 min Olopatadine0.77% 1.5 0.8 65 0 4 Olopatadine 0.2% 1.9 0.7 65 1 4 0.0061 Vehicle 1.90.9 65 1 4 0.0015 Main Effect of Treatment p-value = 0.0004 Treatment byTime Interaction p-value = 0.0077

As can be seen in Table L and FIG. 2, olopatadine at a concentration of0.7% provides statistically significant relief of redness at 16 hoursrelative to both vehicle and olopatadine 2%.

Table M below provides data relative to mean total redness determined bythe CAC study 24 hours after challenge and that data is provided as agraph in FIG. 3. Mean total redness is a summation three rednessdeterminations: i) conjunctival; ii) episcleral; and iii) ciliary, eachtaken on a scale of 1 through 4.

TABLE M Total Redness (24 hrs Duration CAC) By Time Overall Mean Std NMin Max p-value p-value  7 min Olopatadine 0.77% 4.1 2.6 66 0 10Olopatadine 0.2% 5.4 2.4 66 1 11 0.0022 0.0073 Vehicle 6.1 2.3 68 1 10<.0001 <.0001 15 min Olopatadine 0.77% 5.0 2.9 66 0 10 Olopatadine 0.2%6.2 2.3 66 1 11 0.0086 Vehicle 6.7 2.3 68 1 11 <.0001 20 min Olopatadine0.77% 5.4 2.9 66 1 11 Olopatadine 0.2% 6.3 2.3 66 2 11 0.0383 Vehicle6.6 2.6 68 1 11 0.0040 Main Effect of Treatment p-value = 0.0003Treatment by Time Interaction p-value = 0.0136

As can be seen in Table M and FIG. 3, olopatadine at a concentration of0.7% provides statistically significant relief of total redness at 24hours relative to both vehicle and olopatadine 2%.

Table N below provides data relative to ocular itching determined by theCAC study 24 hours after challenge and that data is provided as a graphin FIG. 4.

TABLE N Ocular Itching (24 hrs Duration CAC) By Time Overall Mean Std NMin Max p-value p-value 3 min Olopatadine 0.77% 0.9 0.8 66 0 3Olopatadine 0.2% 1.4 0.8 66 0 3 0.0010 Vehicle 2.5 0.8 68 1 4 <.0001 5min Olopatadine 0.77% 1.1 0.9 66 0 3 Olopatadine 0.2% 1.5 0.9 66 0 40.0107 Vehicle 2.6 0.8 68 0 4 <.0001 7 min Olopatadine 0.77% 1.1 0.9 660 3 Olopatadine 0.2% 1.5 1.0 66 0 4 0.0149 0.0034 Vehicle 2.5 0.9 68 0 4<.0001 <.0001 Main Effect of Treatment p-value = <.0001 Treatment byTime Interaction p-value = 0.3221

As can be seen in Table N and FIG. 4, olopatadine at a concentration of0.7% provides statistically significant relief of ocular itching at 24hours relative to both vehicle and olopatadine 2%.

Table O below provides data relative to ocular itching determined by theCAC study 24 hours after challenge and that data is provided as a graphin FIG. 5.

TABLE O Conjunctival Redness (24 hrs Duration CAC) By Time Overall MeanStd N Min Max p-value p-value  7 min Olopatadine 0.77% 1.5 0.8 66 0 3Olopatadine 0.2% 1.9 0.8 66 0 4 0.0016 0.0075 Vehicle 2.1 0.8 68 1 4<.0001 <.0001 15 min Olopatadine 0.77% 1.8 0.9 66 0 4 Olopatadine 0.2%2.1 0.7 66 0 4 0.0131 Vehicle 2.3 0.7 68 1 4 <.0001 20 min Olopatadine0.77% 1.8 0.9 66 0 4 Olopatadine 0.2% 2.1 0.7 66 1 4 0.0402 Vehicle 2.30.9 68 1 4 0.0024 Main Effect of Treatment p-value = 0.0002 Treatment byTime Interaction p-value = 0.1540

As can be seen in Table O and FIG. %, olopatadine at a concentration of0.7% provides statistically significant relief of conjunctival rednessat 24 hours relative to both vehicle and olopatadine 2%.

We claim:
 1. An aqueous ophthalmic solution for treatment of ocularallergic conjunctivitis, the solution comprising: at least 0.67 w/v %olopatadine dissolved in the solution; PEG having a molecular weight of200 to 800; polyvinylpyrrolidone; a cyclodextrin selected from the groupconsisting of SAE-β-cyclodextrin, hydroxypropyl-β-cyclodextrin andhydroxypropyl-γ-cyclodextrin; and water.
 2. A solution as in claim 1further comprising benzalkonium chloride.
 3. A solution as in claim 2further comprising borate.
 4. A solution as in claim 3 furthercomprising a polyol.
 5. A solution as in claim 1 wherein theconcentration of olopatadine is no greater than 1.0 w/v %.
 6. A solutionas in claim 1 wherein the concentration of PEG is 2.0 w/v % to 6.0 w/v%, the concentration of polyvinylpyrrolidone is 2.0 w/v % to 6.0 w/v %and the concentration of cyclodextrin is at least 0.5 w/v % but nogreater than 2.0 w/v %.
 7. A solution as in claim 1 wherein the solutionprovides more than a 1.0 unit difference relative to vehicle in reliefof redness at onset of action according to FDA accepted CAC model.
 8. Anaqueous ophthalmic solution for treatment of ocular allergicconjunctivitis, the solution comprising: at least 0.67 w/v % olopatadinedissolved in the solution; PEG having a molecular weight of 200 to 800;polyvinylpyrrolidone; a cyclodextrin selected from the group consistingof hydroxybrobyl-β-cyclodextrin and hydroxypropyl-γ-cyclodextrin;benzalkonium chloride; hydroxypropylmethyl cellulose; and water.
 9. Asolution as in claim 8 further comprising borate.
 10. A solution as inclaim 9 further comprising a polyol.
 11. A solution as in claim 8wherein the concentration of olopatadine is no greater than 1.0 w/v %.12. A solution as in claim 8 wherein the concentration of PEG is 2.0 w/v% to 6.0 w/v %, the concentration of polyvinylpyrrolidone is 2.0 w/v %to 6.0 w/v % and the concentration of cyclodextrin is at least 0.5 w/v %but no greater than 2.0 w/v %.
 13. A solution as in claim 8 wherein thesolution provides more than a 1.0 unit difference relative to vehicle inrelief of redness at onset of action according to FDA accepted CACmodel.